The palladium(0) cross-coupling of an aryl halide and an aryl boronic acid (Suzuki reaction) was first described in Synthetic Communications 11:513–519 (1981). Development and application of the reaction have been extensively reviewed. See Acta Chemica Scandanavia 47:221–230(1993); Chemical Reviews 95:2457–2483 (1995); Advances in Metal-Organic Chemistry 6:187–243 (1998).
Sterically hindered examples having three to four substituents ortho to the newly formed biaryl bond continue to be a considerable challenge. The use of aryl chlorides as substrates in the reaction offers three distinct advantages compared to the use of either aryl bromides or aryl triflates. First, the variety of aryl chlorides that are commercially available is much greater than for either the bromides or triflates. Second, use of aryl chlorides offers the greatest atom economy compared to either the bromides or triflates. Third, aryl chlorides are nearly always much cheaper than either the bromides or triflate. See Trost, “The Atom Economy—A Search for Synthetic Efficiency Science,” 254:1471–1477 (1991).
One significant challenge to the use of aryl chlorides is that the oxidative addition of Pd(0) to the arene-chloride bond is very slow compared to the addition across the arene-bromide bond. There are fewer than ten reported examples of the use of aryl chlorides in a sterically hindered Suzuki reaction.
There are two usual sources of Pd(0) for the Suzuki reaction. They are tetrakis-triphenylphosphine palladium and tris-dibenzylideneacetone palladium. Both reagents have the disadvantage of being very air sensitive and, hence, are difficult to handle. Palladium acetate is the only reported salt used in the Suzuki reaction that is air stable. A few papers briefly mention an attempt to use palladium chloride with only minor success because it is polymeric. Palladium chloride is a desirable source of Pd(0) because it is cheaper than palladium acetate.
Pursuant to this invention, an air stable monomer of palladium chloride, viz. palladium chloride cyclooctadiene, is utilized. The exemplified 2-methyl-4-(2,6-dimethylphenyl)indene is a sterically hindered compound. Its synthesis involves the use of an aryl chloride affording the greatest atom economy and lowest cost of material. This new, cheap, air stable source of Pd(0) is shown to be equal to palladium acetate in performance.
U.S. Pat. No. 5,789,634 describes the synthesis of 2-methyl-4-phenylindene by a coupling reaction of phenyl magnesium bromide and 2-methyl-4-chloroindene catalyzed by bis-(1,3-diphenylphosphinopropane) nickel dichloride in 80% isolated yield and in multi-kilogram quantities. However, due to steric hindrance, the analogous reaction as applied to 2-methyl-4-(2,6 dimethylphenyl)indene did not give the desired product. See U.S. Pat. No. 6,291,699 (Col. 7, line 44 to Col. 8, line 3, “Comparative Example 3”).
Examples 1 and 2 of U.S. Pat. No. 6,291,699 illustrate the synthesis of 2-methyl-4-(2,6-dimethylphenyl)indene. The exemplified synthesis requires the use of the costly phosphine ligand 2-dicyclohexylphosphine-2-methyl biphenyl. See J. Org. Chem. 65:1158–1174 (2000) (ligand 5, p. 1160).
Old, et al., J. Am. Chem. Soc. 120:9722–9723 (1998) describes the use of a monophosphine “ligand 2” significantly expands the scope of palladium-catalyzed aryl chloride transformation. The reported formula of “ligand 2” is
wherein PCy2 means dicyclohexyl phosphine. According to Olds, supra, the “ligand 2” was prepared in three steps form N,N-dimethyl-2-bromoaniline.
This invention involves the unexpected discovery that the advantages attributed to “ligand 2” are substantially observed when the structural components of the ligand are concurrently utilized as separate methods in particular catalyzed aryl halide cross-coupling reactions.